This invention relates to novel compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia.
International Patent Application WO 89/05297 discloses a number of substituted quinazoline compounds that are indicated as inhibitors of gastric acid secretion.
Co-pending International Patent Application No. PCT/EP96/05609 discloses a number of quinoline and quinazoline compounds indicated in the treatment of benign prostatic hyperplasia, and discloses 4-amino-6-benzyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline as an intermediate [see Example 49, step (f), therein]. This is the compound of Example 1 of the present application, which is excluded from claim 1 by proviso (b).
According to the present invention, there is provided a compound of formula I, 
wherein
R1 represents C1-4 alkoxy optionally substituted by one or more fluorine atoms;
R2 and R3 independently represent H, C1-6 alkoxy (optionally substituted by one or more fluorine atoms, or by phenyl which may in turn be substituted by one or more fluorine atoms), cyclobutyloxy or CF3CH2O.
R4represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen and NHSO2(C1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms;
X represents CH or N; and
L is absent,
or represents a cyclic group of formula Ia, 
xe2x80x83in which A is attached to R4;
A represents CO or SO2,
Z represents CH or N;
m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and
n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5;
or represents a chain of formula Ib, 
xe2x80x83in which A is attached to R4;
A and Z are as defined above;
R5 and R6 independently represent H or C1-4 alkyl; and
p represents 1, 2 or 3, and in addition, when Z represents CH, it may represent 0;
provided that:
(a) R2 and R3 do not both represent H;
(b) when R1 represents methoxy, R2 represents benzyloxy, R3 represents H, R4 represents morpholinyl, and X represents N, then L is not 
(c) when X represents N and L is absent, then R4 is not naphthyridine;
or a pharmaceutically acceptable salt thereof (referred to together herein as xe2x80x9cthe compounds of the inventionxe2x80x9d).
Alkyl groups may be straight chain, branched, cyclic or a combination thereof. Similarly, the alkyl portion of alkoxy groups may be straight chain, branched, cyclic or a combination thereof.
Preferably, heterocyclic rings represented or comprised by R4 are saturated. Examples include morpholine, tetrahydrofuran and piperidine.
The compounds of the invention may be optically active. The invention includes all optical isomers of the compounds of formula I, and all diastereoisomers thereof.
Preferred groups of compounds that may be mentioned include those in which:
(a) R1 represents methoxy;
(b) R2 represents H or methoxy;
(c) R3 represents cyclobutyloxy or CF3CH2O;
(d) L is absent, in which case R4 preferably represents a piperidine ring which is fused to a pyridine ring or to a benzene ring which is substituted by NHSO2(C1-4 alkyl); and
(e) L represents 
xe2x80x83in which case R4 preferably represents morpholinyl.
When R3 represents H, R2 is preferably benzyloxy or cyclobutyloxy.
According to the invention, there is also provided a process for the production of a compound of the invention, which comprises:
(a) when X represents CH, cyclizing a compound of formula II, 
xe2x80x83in which R1-4 and L are as defined above;
(b) when Z represents N, and L is present, reacting a compound of formula IIIa or IIIb, as appropriate, 
xe2x80x83in which R1, R2, R3, R5, R6, X, m, n and p are as defined above, with a compound of formula IV,
Lgxe2x80x94Axe2x80x94R4xe2x80x83xe2x80x83IV
in which R4 and A are as defined above, and Lg represents a leaving group;
(c) reacting a compound of formula V, 
xe2x80x83in which R1, R4, X and L are as defined above, and Ra and Rb independently represent H or OH, provided that they do not both represent H, with a compound of formula VI,
Rcxe2x80x94Lgxe2x80x83xe2x80x83VI
in which Rc is alkyl (optionally substituted by one or more fluorine atoms, or by pheny which may in turn be substituted by one or more fluorine atoms), and Lg represents a leaving group, in the presence of a base;
(d) when X represents N, reacting a compound of formula VII, 
xe2x80x83in which R1, R2 and R3are as defined above, with a compound of formula VIIIa, VIIIb or VIIIc, as appropriate, 
xe2x80x83in which R4-6, A, Z, m, n and p are as defined above; and R4a has the same significance as R4 above except that it contains a nucleophilic nitrogen atom in the heterocyclic ring which is attached to the H in formula VIIIc;
(e) when A represents CO and R4 comprises a nucleophilic nitrogen atom in the heterocyclic ring attached to L, reacting a compound of formula IXa or IXb, as appropriate, 
xe2x80x83in which R1-3, R5, R6, X, Z, m, n and p are as defined above, and Lg is a leaving group, with a compound of formula VIIIc, as defined above; or
(f) conversion of a compound of formula I in which L represents a cyclic group of formula Ia, to a corresponding compound of formula I in which L represents a chain of formula Ib in which R5 and R6 each represent H, by the action of a strong base; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable salt or vice versa.
In process (a), the cyclization may be carried out in the presence of a strong base (for example lithium diisopropylamide) in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), around room temperature. Alternatively, it may be performed using potassium hydroxide or potassium tert-butoxide in a solvent which does not adversely affect the reaction (for example dimethylsulphoxide or 1,2-dimethoxyethane), at an elevated temperature (for example 80xcex8C). In addition, it may be performed using zinc chloride either without a solvent at an elevated temperature (for example 190xcex8C), or in a solvent which does not adversely affect the reaction (for example dimethylformamide at the reflux temperature of the solvent).
In process (b), suitable leaving groups are OH and Cl. When the compound of formula IV is a carboxylic acid, the reaction may be carried out in the presence of conventional coupling agents [for example 1-hydroxybenzotriazole monohydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-methylmorpholine] in a solvent which does not adversely affect the reaction (for example CH2Cl2) at or around room temperature. When the leaving group is Cl, the reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2 or tetrahydrofuran), around 0xcex8C or up to the reflux temperature of the solvent.
In process (c), suitable leaving groups include halogens such as bromine or iodine, and suitable bases include sodium hydride. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example dimethylformamide) at room temperature or up to the reflux temperature of the solvent.
In process (d), the reaction may be carried out in a solvent which does not adversely affect the reaction (for example n-butanol) in the presence of a base (for example triethylamine) at an elevated temperature (for example the reflux temperature of the solvent).
In process (e), suitable leaving groups include Cl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF) in the presence of a base (for example triethylamine) at room temperature.
The reaction may also be carried out without isolating the compound of formula IXa or IXb, by reacting a compound of formula IIIa or IIIb with triphosgene and a compound of formula VIIIc. In this case the leaving group is xe2x80x94Cl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example CH2Cl2) in the presence of a base (for example triethylamine) at or around room temperature.
In process (f), suitable strong bases include lithium diisopropylamide. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF).
Compounds of formula II [see process (a)] may be prepared by reaction of a compound of formula X, 
in which R1, R2 and R3 are as defined above, with a combination of a compound of formula XI, 
in which R4 and L are as defined above, and phosphorous oxychloride in dichloromethane at the reflux temperature of the solvent.
Compounds of formula X may be prepared from compounds of formula XII, 
in which R1-3 are as defined above, by reaction with Na2S2O4. The reaction may be carried out in a vigorously stirred mixture of dichloromethane and water, at room temperature.
Compounds of formula XII may be prepared from compounds of formula XIII, 
in which R1-3 are as defined above, by reaction with NO2BF4. The reaction may be carried out in acetonitrile at around 0xcex8C.
Alternatively, compounds of formula X may be prepared from compounds of formula XIV, 
in which R1-3 are as defined above, by reaction with (a) magnesium turnings in methanol at room temperature; or (b) triphenylphosphine in tetrahydrofuran at room temperature in the presence of water to form a phosphonimide, followed by acidic hydrolysis.
Compounds of formula XIV may be prepared from compounds of formula XV, 
in which R1-3 are as defined above, by reaction with sodium azide in dimethylformamide, at an elevated temperature (for example 115xcex8C).
Compounds of formula IIIa or IIIb [see process (b)] in which X represents CH may be prepared from compounds of formula XVIa or XVIb, as appropriate, 
in which R1-3, R5, R6, m, n and p are as defined above, by bubbling HCl gas through a solution of the compound in dichloromethane.
Compounds of formula XVIa or XVIb may be prepared from compounds of formula XVIIa or XVIIb, as appropriate, 
in which R1-3, R5, R6, m, n and p are as defined above, by cyclization using potassium hydroxide at an elevated temperature (such as 90xcex8C) in DMSO, quenching with water, or lithium diisopropylamide at room temperature in THF, quenching with water.
Compounds of formula XVIIa or XVIIb may be prepared by reacting a compound of formula X, as defined above, with a compound of formula XVIIIa or XVIIIb, as appropriate, 
in which R5, R6, m, n and p are as defined above, by the method described above for producing compounds of formula II.
Compounds of formula IIIa or IIIb [(see process (b)] in which X represents N may be prepared by reacting a compound of formula VII, as defined above, with a compound of formula XIXa or XIXb, as appropriate, 
in which R5, R6, m, n and p are as defined above, using the conditions mentioned for process (d) above.
Compounds of formula VII may be prepared by conventional means from known compounds (or compounds available using known techniques) according to Scheme 1 below (see also Examples 8 and 9), in which R1-3 are as defined above: 
Compounds of formula V [see process (c)] in which X represents CH may be prepared by cyclization of a compound of formula XX, 
in which R1, R4, Ra, Rb and L are as defined above, using the reaction conditions mentioned in process (a) above.
Compounds of formula XX may be prepared by conventional means from known compounds (or compounds available using known techniques) according to Scheme 2 below [see also Example 1(a)-(c) and Example 6(a)], in which R1, R4, Ra, Rb and L are as defined above: 
Compounds of formula V in which X represents N may be prepared from compounds of formula XXI, 
in which R1, Ra and Rb are as defined above, by reaction with a compound of formula VIIIa, VIIIb or VIIIc, as defined above, as appropriate, using the conditions described in process (d).
Compounds of formula XXI may be prepared by methods analogous to those set out in scheme 1 above for the preparation of compounds of formula VII.
The preparation of compounds of formula VII [see process (d)] has already been described above.
Compounds of formula VIIIa and VIIIb may be prepared by reaction of a compound of formula IV, as defined above, with a compound of formula XIXa or XIXb, as defined above, as appropriate, using the conditions indicated for process (d) above.
Compounds of formula IXa and IXb [see process (e)] in which Lg represents C1 may be prepared from compounds of formula IIIa or IIIb, as defined above, as appropriate, by reaction with triphosgene. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2) in the presence of a base (for example triethylamine) at around xe2x88x9210xcex8C.
Compounds of formulae IV, VI, VIIIc, XI, XIII, XV, XVIIa, XVIIb, XIXa and XIXb are either known or are available using known techniques.
The intermediate compounds of formulae II, IIIa, IIIb, V, VII, IXa and IXb form a further aspect of the invention.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional techniques, for example as described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by T W Greene and P G M Wuts, John Wiley and Sons Inc, 1991.
The compounds of the invention are useful because they possess pharmacological activity in animals. In particular, the compounds are useful in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of particular interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering from such a disorder. The use of the compounds of the invention as pharmaceuticals, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of benign prostatic hyperplasia, are also provided.
The compounds of the invention may be administered by any convenient route, for example orally, parenterally (e.g. intravenously, transdermally) or rectally. The daily dose required will of course vary with the particular compound used, the particular condition being treated and with the severity of that condition. However, in general a total daily dose of from about 0.01 to 10 mg/kg of body weight, and preferably about 0.05 to 1 mg/kg, is suitable, administered from 1 to 4 times a day.
The compounds of the invention will generally be administered in the form of a suitable pharmaceutical formulation. Thus, according to another aspect of the invention, there is provided a pharmaceutical formulation including preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation is preferably in unit dose form. Such forms include solid dosage forms, for example tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical vehicles.
Solid formulations may be prepared by mixing the active ingredient with pharmaceutical carriers, for example conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation formulation in which the active ingredient is uniformly dispersed so that it may be readily subdivided into equally effective unit dosage forms containing typically from 0.1 to about 500 mg of the active ingredient. The solid dosage forms may be coated or otherwise compounded to prolong the action of the formulation.
The formulations of the invention may also contain a human 5-xcex94 reductase inhibitory compound [see International Patent Application WO 95/28397], or a compound of the invention could be presented in a pharmaceutical pack also containing a human 5-xcex94 reductase inhibitory compound as a combined preparation for simultaneous, separate or sequential use.
The compounds of the invention may be tested in the screens set out below.
Contractile Responses of Human Prostate
Prostatic tissue was cut into longitudinal strips (approximately 3xc3x972xc3x9710 mm) and suspended in organ baths under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCl (119), KCl (4.7), CaCl2 (2.5), KH2PO4 (1.2), MgSO4 (1.2), NaHCO3 (25), glucose (11), and gassed with 95% O2/5% CO2.
The solution also contained 10 mM cocaine and 10 mM corticosterone. Tissues were exposed to a sensitising dose of (xe2x88x92)-noradrenaline (100 mM) and washed over a 45 minute period. Isometric contractions were obtained in response to cumulative additions of (xe2x88x92)-noradrenaline to obtain control curves in all tissues. A further curve was then generated in the presence or absence of antagonist (incubated for 2 hours). Antagonist affinity estimates (pA2) were determined using a single concentration of competing antagonist, pA2=xe2x88x92log [A]/(DR-1) where the dose ratio (DR), relative to corresponding controls, was produced by a single concentration of antagonist [A], assuming competitive antagonism and Schild regression close to unity.
Anaesthetised Dog Model of Prostatic Pressure and Blood Pressure
Mature male beagles (12-15 kg body weight) were anaesthetised with sodium pentobarbitone (30-50 mg/kg i.v.) and a tracheal cannula was inserted. Subsequent anaesthesia was maintained using pentobarbitone infusion. The animals were respirated with air using a Bird Mk8 respirator (Bird Corp., Palm Springs, Calif., USA) adjusted to maintain blood gasses in the range pO2 90-110 mm Hg, pCO2 35-45 mm Hg, pH 7.35-7.45. Body temperature was maintained at 36-37.5xcex8C using a heated operating table. Catheters were placed into the left femoral artery for recording blood pressure and into the left femoral vein for compound administration. Heart rate was recorded via the lead II E.C.G. A laparotomy was performed to cannulate both ureters to prevent change of fluid volume within the bladder. A 7F cardiac catheter (with a 1.5 ml capacity balloon tip) was inserted into the bladder via the urethra. The balloon was filled with air and the catheter withdrawn until the balloon became lodged in the prostate, which was confirmed by digital pressure. Balloon pressure was recorded via a Druck transducer. Prostatic pressure and haemodynamic parameters were made on a Grass Polygraph (Grass Instruments, Quincy, Mass., U.S.A.) and the data measured on line using a Motorola 68000-based microcomputer system (Motorola Inc., Temple, Ariz., U.S.A.). Compounds were made up in PEG 300 and administered i.v. through a catheter in the femoral vein. Responses to phenylephrine (1-16 Πg/kg i.v. in saline) were obtained to generate control dose-response curves (two control curves for each experiment). Compounds were administered (in terms of compound base) at 10-300 Πg/kg i.v. 5 min before construction of phenylephrine curves (constructed up to a maximum dose of 128 Πg/kg in the presence of test compound).
Due to xcex941-related dysrhythymic properties of phenylephrine, absolute maximal responses were not obtained but were taken as 10% greater than the control response obtained with 16 Πg/kg phenylephrine. Drug concentrations were calculated on the basis of molar weight of compound/kg body weight thus allowing a xe2x80x9cpseudo pA2xe2x80x9d calculation by Schild analysis using dose ratios derived from shifts in the phenylephrine dose-response curves.
The compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective (in particular they may have beneficial effects in benign prostatic hyperplasia without causing undesirable cardiovascular effects, for example because they are able to selectively antagonise prostatic receptor subtypes of the Al-adrenoceptor), or have other more useful properties than the compounds of the prior art.